The long-term goal of this research project is to develop effective strategies for the prevention of prostate cancer progression to androgen independence. Our approach to the effective prevention of androgen independence is the use of suitable combinations of preventive agents that target critical survival pathways for prostate cancer cells such as the Akt and MAP kinase pathways. Preliminary studies from our laboratory showed that a cholesterol-lowering drug Lipitor (atorvastatin) in combination with the cyclooxygenase-2 (Cox-2) inhibitor Celebrex (celecoxib) strongly inhibited the growth and induced apoptosis in prostate cancer cells and this combination inhibited the growth of androgen-independent prostate tumors in immunodeficient mice more effectively than either agent alone. We propose to study the effect of Lipitor in combination with Celebrex in preventing prostate cancer progression to androgen independence. The specific aims are: (1) Determine the preventive effects of Lipitor in combination with Celebrex on the progression of androgen-dependent LNCaP and CWR22Rv1 prostate cancer cells to androgen independence. We will determine the potential synergistic effects of Lipitor and Celebrex in combination on the growth and apoptosis of LNCaP and CWR22Rv1 cells cultured in androgen-depleted medium. (2) Study the mechanism by which Lipitor in combination with Celebrex synergistically inhibit the growth and induce apoptosis in LNCaP and CWR22Rv1 cells. We will specifically determine if the concurrent inhibition of Akt and p44/42 MAP kinase activation by Lipitor and Celebrex in combination is associated with synergistic induction of apoptosis in LNCaP and.CWR22Rv1 cells cultured in androgen-depleted medium. (3) Determine the effect of Lipitor and Celebrex in preventing/delaying the development of androgen-independent growth in LNCaP xenograft tumors in immunodeficient mice. Although many agents have been shown to have the potential for suppressing the progression of prostate cancer, toxic side effects may limit the clinical application of these agents. We anticipate that completion of the studies proposed here will provide compelling evidence that an aggregate action of low doses of Lipitor and Celebrex in combination will strongly inhibit prostate cancer progression, while the side effects induced by Lipitor and Celebrex will be minimized. This combination of drugs may significantly improve the management of prostate cancer. [unreadable] [unreadable] [unreadable]